Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease or motor neuron disease (MND), is one of several neurodegenerative diseases of the central nervous system. ALS is the most common adult onset motor neuron disease, affecting one in every 20,000 individuals, with an average age of onset of 50-55 years. ALS is characterized by rapidly progressive degeneration of motor neurons in the brain, brainstem, and spinal cord (Cleveland et al., Nat. Rev. Neurosci., 2:806-19 (2001)). The median survival of patients from time of diagnosis is five years.
ALS exists in both sporadic and familial forms. Only 5-10% of all ALS cases are Familial ALS (FALS). Over the last decade, a number of basic and clinical research studies have focused on understanding the familial form of the disease, which has led to the identification of eight genetic mutations related to FALS. Transgenic mice expressing point mutants of the Cu/Zn superoxide dismutase-1 (SOD1) gene develop an age-dependent progressive motor weakness similar to human ALS due to a toxic gain of function (Rosen et al., Nature, 362:59-62 (1993); Rosen et al., Hum Mol Genet, 3, 981-987 (1994)).
These genetic mutations, however, do not explain sporadic ALS (SALS). The pathogenesis of SALS is multifactorial. A number of different model systems, including SOD1 transgenic mice, in vitro primary motor neuron cultures or spinal cord slice cultures, in vivo imaging studies, and postmortem examination of tissue samples, have been utilized to understand the pathogenesis of ALS (Subramaniam et al., Nat. Neurosci., 5:301-307 (2002)). Although these studies have yielded therapeutic targets and several clinical trials, there are no drugs that delay disease onset or prolong long-term survival of ALS patients. Riluzole (Rilutek®, Aventis), a glutamate antagonist, currently is the only FDA-approved medication available to treat ALS. Riluzole, however, extends life expectancy by only a few months (Miller et al., Amyotrophic Lateral Sclerosis & Other Motor Neuron Disorders, 4, 191-206 (2003).). Creatine and a-tocopherol have shown some efficacy in relieving the symptoms of ALS in SOD1 transgenic mice, but exhibit minimal efficacy in human ALS patients (Groeneveld et al., Annals of Neurology, 53:437-45 (2003).
Studies have been performed which have identified early protein biomarkers for ALS, using mass spectrometry based proteomics of cerebrospinal fluid (CSF) and spinal cord samples of human subjects. For example, three neuroendocrine proteins (transthyretin, 7B2, and cystatin C) that exhibit alterations early in the disease pathogenesis in humans were identified in a proteomics analysis (US 20060178306 to Bowser).
Cystatin C has been identified using mass spectrometry as a diagnostic biomarker for ALS. CSF and lumbar spinal cord tissue samples from ALS subjects exhibit less cystatin C than control subjects. Cystatin C is a secreted protein that functions both as a cysteine protease inhibitor and can function as an autocrine or paracrine factor in neurogenesis of neural stem cells. Mutations in the cystatin C gene cause a rare disease called hereditary brain amyloid angiopathy, and increased levels of cystatin C have been found in other neurodegenerative diseases including Alzheimer's disease, ischemia, and Creutzfeldt-Jakob disease (CJD). Decreased levels of cystatin C in the CSF of ALS subjects or altered post-translational modifications to cystatin C suggest decreased levels of protease inhibitors, which may contribute to disease pathogenesis.
Despite the identification of early protein biomarkers for ALS, there remains a need, however, for improved methods for identifying therapeutic targets of ALS, and improved methods of diagnosing and monitoring the progress of the disease.
Therefore, it is an object of the invention to provide methods for diagnosing and monitoring ALS.
It is still another object to provide biomarkers for monitoring the progression of ALS.
It is another embodiment to provide methods and compositions for identifying agents for the treatment of ALS.